Wang David, Jackson Chris, Hung Noelyn, Hung Tak, Kwan Rudolf, Chan Wing-Kai, Qin Albert, Hughes-Medlicott Natalie J, Glue Paul, Duffull Stephen
Department of Anaesthesia, Waikato Hospital, Hamilton, New Zealand.
Department of Medicine, University of Otago, Dunedin, New Zealand.
J Pharmacokinet Pharmacodyn. 2024 Aug;51(4):335-352. doi: 10.1007/s10928-024-09913-y. Epub 2024 Mar 19.
The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency.
A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision.
The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels.
The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.
优化给药方案的制定在肿瘤药物研发中起着至关重要的作用。本研究聚焦于多西他赛的群体药代动力学建模与模拟，比较口服多西他赛加恩喹哒（oDox + E）与标准静脉注射（IV）多西他赛方案的药代动力学暴露情况。目的是评估oDox + E作为IV多西他赛潜在替代方案的可行性。本文展示了一种与美国食品药品监督管理局（FDA）的“擎天柱计划”相一致的方法，该计划旨在通过模型引导药物研发（MIDD）改善肿瘤药物研发。本研究回答的关键问题是是否存在可行的oDox + E方案。提出这个问题的目的是提供一个早期的“继续/停止”决策点，以指导药物研发并提高研发效率。
采用逐步方法建立IV多西他赛和oDox + E给药后多西他赛总血浆浓度和游离血浆浓度的群体药代动力学模型。根据最终模型进行模拟，使用一系列有效浓度（EC）下的AUC超过有效浓度（AUCOEC）指标，评估不同oDox + E剂量方案（包括多剂量方案）相对于IV多西他赛达到目标的概率（PTA）。定义了一个“继续/停止”框架——框架的第一部分评估是否存在可行的oDox + E方案（即PTA≥80%），第二部分定义做出“继续”决策的条件。
总体群体药代动力学模型由一个具有线性消除、恒定生物利用度、恒定结合机制和组合误差模型的三室模型组成。模拟结果显示，单剂量oDox + E方案的PTA未超过80%。然而，600毫克的两剂量和三剂量方案在某些EC水平下的PTA超过了80%。
本研究以oDox + E为例证明了MIDD的益处。建立了IV多西他赛和oDox + E给药后多西他赛血浆总浓度和游离浓度的群体药代动力学模型。该模型用于模拟oDox + E剂量方案，并与当前标准护理IV多西他赛方案进行比较。应用“继续/停止”框架来确定oDox + E是否应进入药物研发的下一阶段以及是否应适用任何条件。在模拟中，600毫克的两剂量或三剂量oDox + E方案能够实现与当前标准护理IV多西他赛非劣效的药代动力学暴露。基于这一结果做出了有条件的“继续”决策，进一步量化“有效浓度”将提高优化剂量方案的能力。
